There are 3 million Americans with epilepsy. This research aims to develop first-in-class drug- inducible gene therapies for the most common form of focal epilepsy, temporal lobe epilepsy (TLE), which affects half a million Americans. Despite the size of this problem, medical treatment of TLE fails in 35% of these patients, leaving a large unmet clinical need. For over 40 years, the only option left for some of these patients has been surgical resection of the temporal lobe. Although this reduces seizures, it has many problems. One, it is not a cure, so most patients must continue to take antiepileptic drugs with attendant side effects. Two, many patients are unwilling to take the risk of permanent brain damage, such as impaired learning and memory. TLE is one of the best studied forms of epilepsy and there are excellent animal models of TLE that can be used to test novel therapies. The overarching hypothesis of this grant is that by silencing critical neurons in the epileptic circuit with gene therapy, one can effectively stop seizures cold. This approach could be extended to other types of focal seizures, such as: focal cortical dysplasia and epilepsy after traumatic brain injury. Notably, this treatment could be used on patients for whom surgery is not an option due to fear of neurological deficits, those with multiple seizure foci or when the focus is in a critical, or ?eloquent? region of the cortex. To address this critical unmet need, this grant will develop novel gene therapies based on recombinant adeno-associated virus (AAV). Advances in imaging and EEG source localization already allow doctors to localize seizure foci almost to the cellular level. Imagine a future when, rather than cutting, neurosurgeons inject AAV to disrupt the seizure from spreading to the rest of the brain. In fact, magnetic resonance imaging (MRI)-guided delivery of therapeutics has already been shown to be an effective method for targeting specific brain regions. Using funds from the CURE Foundation, preliminary data was collected that show AAV delivery of a modified leak K+ channel (TREK-M) reduces status epilepticus. Importantly, the gene therapy reduced spontaneous recurring seizures by 90% in a rat model of TLE. Aim 1 will compare injection of TREK-M at different sites and study its effect on spontaneous seizures in a chronic TLE rat model. Aim 2 will test the safety of the gene therapy in control animals and whether TREK-M can correct seizure-induced deficits in learning and memory. Aim 3 is a preclinical study to establish the efficacy of the gene therapy on spontaneous recurring seizures in a rat model of TLE. We predict drug-inducible gene therapy will have a large impact on both clinical and basic research.